Quality by Design An Attempt to Jumpstart Innovation Into the

Document Sample
Quality by Design An Attempt to Jumpstart Innovation Into the Powered By Docstoc
					Quality by Design: An Attempt to Jumpstart
Innovation Into the Manufacturing Process
           Peter Calcott, Ph.D.
       President, Calcott Consulting




                     GMP in the 21st Century


 • Quality by Design (QbD) is part of Critical
   P th initiative and GMP’ i 21st century
   Path i iti ti     d GMP’s in        t
   driven by FDA
 • Driven by resources
      –   Small increase in FDA staff and dollars
      –   PDUFA restrictions and guarantees
      –   I         i       l
          Increase in supplements t
      –   In spite of slowing of New Molecular Entity
          approval

calcott consulting




                                                        1
             What is “Quality by Design”?


 • Quality
      – “Good pharmaceutical quality represents an
        acceptably low risk of failing to achieve the
        desired clinical attributes.”
 • QbD
      – “Means that product and process performance
        characteristics are scientifically designed to
                      objectives,
        meet specific objectives not merely
        empirically derived from performance of test
        batches.”
                                              Janet Woodcock (2004)


calcott consulting




  Linking Structure, Function and Controls

 • In a QbD system:
      – The product is designed to meet patient needs and
        performance requirements
      – The process is designed to consistently meet product
        critical quality attributes
      – The impact of starting raw materials and process
        parameters on product quality is understood
      – The process is continually monitored, evaluated and
        updated to allow for consistent quality over time
                                      y
      – Critical sources of variability are identified and
        controlled
 • Appropriate control strategies developed

                               Duffy (2007)
calcott consulting




                                                                      2
        Quality, Continuous Improvement
             Process (CIP) and QbD
• Proactive approach to continual improvement and
  innovation instead of reactive compliance
          h
  approaches
• Manufacturing experience and knowledge provides
  opportunity to evaluate and improve processes
• Manufacturing experience and product knowledge
  can be used to establish a “design space”
• Introduction of innovative processes and controls is
  encouraged and will be facilitated
• Robust Pharmaceutical Quality System (PQS) is
  essential to implement scientific risk based change
  control
                           Duffy (2007)
calcott consulting




                QbD and Linkage into ICH


   Q     y     g
 • Quality Design
      – Not testing in but creating quality by
        designing in

      – Linked very much with ICH Q8, 9, 10

      – Heavy into CIP and risk


calcott consulting




                                                         3
                       ICH Q8, Q9 & Q10



 • Q8 – Pharmaceutical development

 • Q9 – Risk based judgment

 • Q10 – Quality Systems – inc CIP



calcott consulting




                     Not all QbD is the Same

 • Principle behind is really to understand what
   makes good products and then make sure
   process is within areas of success to yield
   good product
      – For drugs easily understood
          • Tablet properties, API is very clearly defined
      – For biologics less easily understood
          • Characterisation less than complete,
            immunogenicity, carbohydrate changes
            i          i it     b h d t h
 • From this key parameters that govern Critical
   Quality Attributes (CQA)
 • Process topology / topography
calcott consulting




                                                             4
        QbD can lead to Regulatory Relief


 • Good product CQA           process parameters
       process controls and inputs
 • Process topology/topography understanding
 • Define process controls and inputs
   process parameters        CQA      good product
 • If that done will get regulatory relief and this
   helps industry and regulatory bodies
 • Less number of supplements
      – Simpler and less demanding supplements
      – Less number of and shorter inspections
calcott consulting




                     Regulatory Relief


 • PAS                      PAI/PLI/biennial

 • CBE 0                    decrease length

 • CBE 30                   elimination

 • AR                       reduced cycle

 • NR
calcott consulting




                                                      5
                     Linkages



       Safety                          Manufact.
                                       M   f t
       Efficacy                        Process
        (SE)                             (MP)



                      Quality
                     Attributes
                       (QA)
calcott consulting




  Continuous Improvement Links into QbD




                     Quality
                       by
                     Design




calcott consulting
                                  Duffy (2007)




                                                   6
                       Operations



                         SPECS


                       VALIDATION


                     CHARACTERISATION

                 RESEARCH & DEVELOPMENT


calcott consulting




           Two Issues for Success of QbD


 • It is really two fold
        1 – do we understand the process
        landscape? – science
        2 – can we communicate it effectively?
          • Can we tell the story?
          • Is it believed?
          • This is communication and trust



calcott consulting




                                                 7
        Generics, Drugs and Biologics are
                    Different

 • QbD not the same for generics, drugs and
   biologics
 • Generics – same compound, specs approval.
   Little process development, just confirming.
   Little understanding of Quality attributes.
 • For generics – science is the issue
 • Changes are quite laborious and dependent
   on the established drug
 • Drugs and biologics more complex approvals
 • Generics Drugs Biologics
calcott consulting




                     Generics Approach


 • Quality by Review (QbR) has made FDA’s
         t ti     l       limited      i
   expectations clearer - li it d experience
 • Guides product and process development
 • Promotes communication among different
   functions within the company
 • Points to the need for good knowledge
   management systems
 • Will and should improve technology transfer

                            Mundkur et al. (2007)
calcott consulting




                                                    8
               Generics Approach (cont.)

 • QbR questions have changed the information
   g        g            p    g generic drug
   gathering and data reporting of g             g
   development
 • Move development activities upfront; more
   product and process understanding reduces
   risk of process scale-up
 • Technical support and technical writers
   added
 • Deficiency questions are science-based and
   are used to re-direct R&D activity for future
   ANDAs
                          Mundkur et al. (2007)
calcott consulting




               Generics Approach (cont.)


 • QbR encourages forward thinking of QbD
   elements and principles
 • Define the target of generic product quality
   profile pharmaceutically equivalent to drug
 • Understanding of properties of drug
   substance and product design
 • Understanding of manufacturing process
 • Development report is now more product and
   process design focused

                          Mundkur et al. (2007)
calcott consulting




                                                     9
               Generics Approach (cont.)


    • QbR has changed the quality
      assessment within OGD and has
      generated positive comments from the
      reviewers
    • Office of Generic Drug (OGD) stated
      that QbR is being developed for
      microbiology review and to a certain
      degree, bioequivalence review
                             Mundkur et al. (2007)
calcott consulting




                     Generics Next Steps

•    How much more information and knowledge on
    development activities is needed for filing?
•    M      l it f FDA’s         t ti
     More clarity of FDA’ expectation
•    Developing a risk based approach to achieve
    OGD’s goal of up to 80% CMC supplement reduction
•    Develop metrics beyond the preliminary risk
    assessment strategy proposed by OGD
•    Can post-approval data be evaluated upon review
    or inspection and used for regulatory relief?
•    For some sponsors, additional development work
    (e.g. process) will be needed to fully address QbR
    prior to submission
                             Mundkur et al. (2007)
calcott consulting




                                                         10
                         Drugs


 • Science is there
 • Issue is communication and trust
 • Develop NDA that is comprehensive
   and science driven
 • Success story for some innovators



calcott consulting




                     Drugs Next Steps

 • Drugs – processes are simpler than biologics
         p
 • Unit operations
      – API – properties, RM for next step, granulation,
        physical properties, how much variability is
        acceptable for next step – edge of failure
      – Granulated API – tabletting to get quality
        properties
      – Tablet properties
      – Controlled delivery devices and prolonged
        release formulations
 • Pfizer has successfully done this – relief from
   inspection for drugs
calcott consulting




                                                           11
         Drugs versus biologics




calcott consulting




                     QbD for Biologics


 • Biologics – much more complex
   process
      – Cell bank to fermentation to Biological
        Drug Substance to vialed product
      – Again – unit operation – RM controls and
        end product for next step
 • QbD is not new for biologics – without it
   we would not have processes.

calcott consulting




                                                   12
                     What are the issues?


 • For biologics, issues surface
      – Lack of complete characterisation – structure
        not 100% known
      – Lack of linkage of Bioactivity measurement
        and chemical potency
      – Significant change in chemistry
        (carbohydrate/glycosylation) yet no change in
        p      y                  g
        potency and also no changes seen in
        chemistry but potency changes seen
      – Changes in immunologic reactions – relevance
      – Pharmacodynamic/Pharmacokinetic
        differences
calcott consulting




               The Real Underlying Issue


 • Biologics issue is science, communication
     d trust
   and t t
 • For well characterised products comparability
   protocols step in right direction – partly QbD –
   predicting outcomes
 • QbD – Genentech and others are doing this
   but till       k in
   b t still a work i progress
 • Generic biologics will challenge the paradigm


calcott consulting




                                                        13
        Quality Life Cycle by Kozlowski (2007)

                         Design - Evaluation       Identify – key /
                               p
                            Propose                Critical - Ranges &
                   (Desired Attributes/Process)    Parameters
                                                     Development
Optimize                                                     (DOE)
                                                     Studies (DOE)
(Continuous                Knowledge Base
Improvement
                           Product-specific
Innovation)
                           Process-specific
                            Q lit Ri k
                            Quality Risks           Confirm
                                                  (Control/ Predict)
                                                    Conformance Lots
  Monitor                                           “Validation Studies”
 Post-
 Post-Approval
                             Commercial
    calcott consulting       Production




                         Take Home Messages


   • QbD is different in industry (generics biologics)
           hil     h leads to
   • QbD philosophy l d t
       – Stronger linkage between departments within
         companies
       – Improved success in product approval
       – More robust, efficient commercial operations
       – Decreased production failures
       – Decreased regulatory burden
       – Improved relationship with regulatory bodies
       – Science driven compliance

    calcott consulting




                                                                           14
                                 Q&A




             Any questions?



calcott consulting




                       Calcott Consulting

                     Peter Calcott, Ph.D
                President, Calcott Consulting
                         ,                  g
                     Consultant to the Pharmaceutical &
                          Biotechnology Industry


                      Office: 510-527-2662
                      Mobile: 510-585-8256

         Email: peterc@calcott-consulting.com
         Website: www.calcott-consulting.com
calcott consulting




                                                          15

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:14
posted:8/10/2011
language:English
pages:15